Chlorambucil is rapidly and completely absorbed from the gastrointestinal tract. After single oral doses of 0.6 to 1.2 mg/kg, peak plasma chlorambucil levels (Cmax) are reached within 1 hour and the terminal elimination half-life (t½) of the parent drug is estimated at 1.5 hours. Chlorambucil undergoes rapid metabolism to phenylacetic acid mustard, the major metabolite, and the combined chlorambucil and phenylacetic acid mustard urinary excretion is extremely low — less than 1% in 24 hours. In a study of 12 patients given single oral doses of 0.2 mg/kg of LEUKERAN, the mean dose (12 mg) adjusted (± SD) plasma chlorambucil Cmax was 492 ± 160 ng/mL, the AUC was 883 ± 329 ng•h/mL, t½ was 1.3 ± 0.5 hours, and the tmax was 0.83 ± 0.53 hours. For the major metabolite, phenylacetic acid mustard, the mean dose (12 mg) adjusted (± SD) plasma Cmax was 306 ± 73 ng/mL, the AUC was 1204 ± 285 ng•h/mL, the t½ was 1.8 ± 0.4 hours, and the tmax was 1.9 ± 0.7 hours.

Chlorambucil and its metabolites are extensively bound to plasma and tissue proteins. In vitro, chlorambucil is 99% bound to plasma proteins, specifically albumin. Cerebrospinal fluid levels of chlorambucil have not been determined. Evidence of human teratogenicity suggests that the drug crosses the placenta.

Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard, which has antineoplastic activity. Chlorambucil and its major metabolite spontaneously degrade in vivoforming monohydroxy and dihydroxy derivatives. After a single dose of radiolabeled chlorambucil (¹⁴C), approximately 15% to 60% of the radioactivity appears in the urine after 24 hours. Again, less than 1% of the urinary radioactivity is in the form of chlorambucil or phenylacetic acid mustard. In summary, the pharmacokinetic data suggest that oral chlorambucil undergoes rapid gastrointestinal absorption and plasma clearance and that it is almost completely metabolized, having extremely low urinary excretion.

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